Targeting active RAS with molecular glue

Abstract

Activating mutations in RAS genes, notably KRASG12C, are pervasive in numerous cancers, presenting formidable challenges to therapy due to their elusive druggability. The landmark discovery of KRASG12C allosteric inhibitors marked a transformative milestone in cancer treatment, resulting in the approval of sotorasib and adagrasib. However, limitations in the depth and duration of response prompted the quest for alternative strategies. Recently, Holderfield et al., Wasko et al., and Jiang et al. reported on tri-complex inhibitors, namely RMC-7977 and RMC-6236, targeting activated RAS variants, demonstrating promising preclinical efficacy surpassing adagrasib. These advancments signify a paradigm shift in RAS oncology, promising enduring therapeutic benefits and warranting further clinical exploration.

Data availability

Not applicable.

Ethics approval

Not applicable.

Funding information

This work was partly supported by the National Key R&D Program of China (2022YFA1305800), the National Natural Science Foundation of China (32370754), and the Shandong Provincial Youth Innovation Team Development Program (2023KJ026).

CRediT authorship contribution statement

Wenjing Su: Writing - original draft, Conceptualization. Xuben Hou: Writing - review & editing, Visualization.

Declaration of competing interest

The author declare no conflict of interests.

Acknowledgments

Not applicable.

References

[1] M. Holderfield, B.J. Lee, J. Jiang, A. Tomlinson, K.J. Seamon, A. Mira, E. Patrucco, G. Goodhart, J. Dilly, Y. Gindin, N. Dinglasan, Y. Wang, L.P. Lai, S. Cai, L. Jiang, N. Nasholm, N. Shifrin, C. Blaj, H. Shah, J.W. Evans, N. Montazer, O. Lai, J. Shi, E. Ahler, E. Quintana, S. Chang, A. Salvador, A. Marquez, J. Cregg, Y. Liu, A. Milin, A. Chen, T.B. Ziv, D. Parsons, J.E. Knox, J.E. Klomp, J. Roth, M. Rees, M. Ronan, A. Cuevas-Navarro, F. Hu, P. Lito, D. Santamaria, A.J. Aguirre, A.M. Waters, C.J. Der, C. Ambrogio, Z. Wang, A.L. Gill, E.S. Koltun, J.A.M. Smith, D. Wildes, M. Singh, Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy, Nature 629 (2024) 919-926, https://doi.org/10.1038/s41586-024-07205-6.

[2] U.N. Wasko, J. Jiang, T.C. Dalton, A. Curiel-Garcia, A.C. Edwards, Y. Wang, B. Lee, M. Orlen, S. Tian, C.A. Stalnecker, K. Drizyte-Miller, M. Menard, J. Dilly, S.A. Sastra, C.F. Palermo, M.C. Hasselluhn, A.R. Decker-Farrell, S. Chang, L. Jiang, X. Wei, Y.C. Yang, C. Helland, H. Courtney, Y. Gindin, K. Muonio, R. Zhao, S.B. Kemp, C. Clendenin, R. Sor, W.P. Vostrejs, P.S. Hibshman, A.M. Amparo, C. Hennessey, M.G. Rees, M.M. Ronan, J.A. Roth, J. Brodbeck, L. Tomassoni, B. Bakir, N.D. Socci, L.E. Herring, N.K. Barker, J. Wang, J.M. Cleary, B.M. Wolpin, J.A. Chabot, M.D. Kluger, G.A. Manji, K.Y. Tsai, M. Sekulic, S.M. Lagana, A. Califano, E. Quintana, Z. Wang, J.A.M. Smith, M. Holderfield, D. Wildes, S.W. Lowe, M.A. Badgley, A.J. Aguirre, R.H. Vonderheide, B.Z. Stanger, T. Baslan, C.J. Der, M. Singh, K.P. Olive, Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer, Nature 629 (2024) 927-936, https://doi.org/10.1038/s41586-024-07379-z.

[3] J. Jiang, L. Jiang, B.J. Maldonato, Y. Wang, M. Holderfield, I. Aronchik, I.P. Winters, Z. Salman, C. Blaj, M. Menard, J. Brodbeck, Z. Chen, X. Wei, M.J. Rosen, Y. Gindin, B.J. Lee, J.W. Evans, S. Chang, Z. Wang, K.J. Seamon, D. Parsons, J. Cregg, A. Marquez, A.C.A. Tomlinson, J.K. Yano, J.E. Knox, E. Quintana, A.J. Aguirre, K.C. Arbour, A. Reed, W.C. Gustafson, A.L. Gill, E.S. Koltun, D. Wildes, J.A.M. Smith, Z. Wang, M. Singh, Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers, Cancer Discov (2024) OF1-OF24. https://doi.org/10.1158/2159-8290.CD-24-0027.

[4] J.M. Ostrem, U. Peters, M.L. Sos, J.A. Wells, K.M. Shokat, K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions, Nature 503 (2013) 548-551. https://doi.org/10.1038/nature12796.

[5] D. Kim, L. Herdeis, D. Rudolph, Y. Zhao, J. Bottcher, A. Vides, C.I. Ayala-Santos, Y. Pourfarjam, A. Cuevas-Navarro, J.Y. Xue, A. Mantoulidis, J. Broker, T. Wunberg, O. Schaaf, J. Popow, B. Wolkerstorfer, K.G. Kropatsch, R. Qu, E. de Stanchina, B. Sang, C. Li, D.B. McConnell, N. Kraut, P. Lito, Pan-KRAS inhibitor disables oncogenic signalling and tumour growth, Nature 619 (2023) 160-166. https://doi.org/10.1038/s41586-023-06123-3.

[6] Q. Zheng, Z. Zhang, K.Z. Guiley, K.M. Shokat, Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D, Nat. Chem. Biol. (2024). https://doi.org/10.1038/s41589-024-01565-w.

[7] X. Wang, S. Allen, J.F. Blake, V. Bowcut, D.M. Briere, A. Calinisan, J.R. Dahlke, J.B. Fell, J.P. Fischer, R.J. Gunn, J. Hallin, J. Laguer, J.D. Lawson, J. Medwid, B. Newhouse, P. Nguyen, J.M. O’Leary, P. Olson, S. Pajk, L. Rahbaek, M. Rodriguez, C.R. Smith, T.P. Tang, N.C. Thomas, D. Vanderpool, G.P. Vigers, J.G. Christensen, M.A. Marx, Identification of MRTX1133, a noncovalent, potent, and selective KRAS(G12D) inhibitor, J. Med. Chem. 65 (2022) 3123-3133. https://doi.org/10.1021/acs.jmedchem.1c01688.

[8] J.Y. Xue, Y. Zhao, J. Aronowitz, T.T. Mai, A. Vides, B. Qeriqi, D. Kim, C. Li, E. de Stanchina, L. Mazutis, D. Risso, P. Lito, Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition, Nature 577 (2020) 421-425. https://doi.org/10.1038/s41586-019-1884-x.

[9] M.M. Awad, S. Liu, I.I. Rybkin, K.C. Arbour, J. Dilly, V.W. Zhu, M.L. Johnson, R.S. Heist, T. Patil, G.J. Riely, J.O. Jacobson, X. Yang, N.S. Persky, D.E. Root, K.E. Lowder, H. Feng, S.S. Zhang, K.M. Haigis, Y.P. Hung, L.M. Sholl, B.M. Wolpin, J. Wiese, J. Christiansen, J. Lee, A.B. Schrock, L.P. Lim, K. Garg, M. Li, L.D. Engstrom, L. Waters, J.D. Lawson, P. Olson, P. Lito, S.I. Ou, J.G. Christensen, P.A. Janne, A.J. Aguirre, Acquired resistance to KRAS(G12C) inhibition in cancer, N. Engl. J. Med. 384 (2021) 2382-2393. https://doi.org/10.1056/NEJMoa2105281.

[10] Y. Zhao, Y.R. Murciano-Goroff, J.Y. Xue, A. Ang, J. Lucas, T.T. Mai, A.F. Da Cruz Paula, A.Y. Saiki, D. Mohn, P. Achanta, A.E. Sisk, K.S. Arora, R.S. Roy, D. Kim, C. Li, L.P. Lim, M. Li, A. Bahr, B.R. Loomis, E. de Stanchina, J.S. Reis-Filho, B. Weigelt, M. Berger, G. Riely, K.C. Arbour, J.R. Lipford, B.T. Li, P. Lito, Diverse alterations associated with resistance to KRAS(G12C) inhibition, Nature 599 (2021) 679-683. https://doi.org/10.1038/s41586-021-04065-2.

[11] M.B. Ryan, F. Fece de la Cruz, S. Phat, D.T. Myers, E. Wong, H.A. Shahzade, C.B. Hong, R.B. Corcoran, Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition, Clin. Cancer Res. 26 (2020) 1633-1643. https://doi.org/10.1158/1078-0432.CCR-19-3523.

[12] N. Tanaka, J.J. Lin, C. Li, M.B. Ryan, J. Zhang, L.A. Kiedrowski, A.G. Michel, M.U. Syed, K.A. Fella, M. Sakhi, I. Baiev, D. Juric, J.F. Gainor, S.J. Klempner, J.K. Lennerz, G. Siravegna, L. Bar-Peled, A.N. Hata, R.S. Heist, R.B. Corcoran, Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation, Cancer Discov 11 (2021) 1913-1922. https://doi.org/10.1158/2159-8290.CD-21-0365.

[13] C.J. Schulze, K.J. Seamon, Y. Zhao, Y.C. Yang, J. Cregg, D. Kim, A. Tomlinson, T.J. Choy, Z. Wang, B. Sang, Y. Pourfarjam, J. Lucas, A. Cuevas-Navarro, C. Ayala- Santos, A. Vides, C. Li, A. Marquez, M. Zhong, V. Vemulapalli, C. Weller, A. Gould, D.M. Whalen, A. Salvador, A. Milin, M. Saldajeno-Concar, N. Dinglasan, A. Chen, J. Evans, J.E. Knox, E.S. Koltun, M. Singh, R. Nichols, D. Wildes, A.L. Gill, J.A.M. Smith, P. Lito, Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS, Science 381 (2023) 794-799. https://doi.org/10.1126/science.adg9652.

[14] P.A. Jänne, F. Bigot, K. Papadopoulos, L. Eberst, D. Sommerhalder, L. Lebellec, P.J. Voon, B. Pellini, E. Kalinka, K. Arbour, B. Herzberg, V. Boni, S. Bordenave, H.W. Lee, S.I. Ou, J.W. Riess, J.T. Beck, M. Ponz-Sarvise, P.A. Ascierto, Y.J. Choi, M. Yang, L. Bao, R. Raman, L.X. Yang, Y.M. Mu, S. Wong, R. Dua, M. Johnson, Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRAS(ON) inhibitor, in patients with or without prior KRAS(OFF) inhibitor treatment, Mol. Cancer Therapeut. 22 (2023) PR014. https://doi.org/10.1158/1535-7163.TARG-23-PR014.